ISSN 0012-5008, Doklady Chemistry, 2008, Vol. 423, Part 1, pp. 279–282. © Pleiades Publishing, Ltd., 2008.Original Russian Text © I.N. Shishkina, V.M. Dem’yanovich, A.A. Kuznetsova, K.A. Potekhin, N.S. Zefirov, 2008, published in Doklady Akademii Nauk, 2008, Vol. 423, No. 1,pp. 72–75.

279

Recent years have seen revived interest in the syn-thesis of organofluorine compounds, which is due to thespecific ability of fluorine atoms to change consider-ably physicochemical and biological properties of com-pounds. Organofluorine compounds have found impor-tant applications in various fields such as design ofnovel materials and production of agrochemical agentsand drugs [1, 2]. Their use is markedly restricted by thedifficulty of their synthesis.

Previously, we proposed the synthesis of chiral dia-stereomeric fluorine-containing amino alcohols from(

S

)-

N

,

N

-dimethyl-1-phenylethylamine (

1

) through

ortho

-lithiation followed by condensation with phenyltrifluoromethyl ketone [3]. We also developed a methodfor the synthesis of

ortho-

keto-substituted

1

by the

reaction of

ortho-

lithiated

1

(

1a

) with acyl chlorides [4]and esters. The ketones thus obtained are good interme-diates in the synthesis of more complex bi- and trifunc-tional chiral compounds.

Here we studied the reactions of

1a

with ethyl triflu-oroacetate and heptafluorobutyrate to obtain the corre-sponding ketones and convert them into fluorine-con-taining diamines, amino alcohols, and heterocycles.These fluorinated ketones can also be of interest them-selves, as some trifluoroacetophenones are known toinhibit acetylcholine esterase [5]. However, the out-come of the reaction was unexpected: condensation of

1a

with esters of perfluorinated acids gave fluorinatedsecondary alcohols instead of the expected ketones(Scheme 1).

Scheme 1.

NMe2

H Me

NMe2

H Me

OH

C3F7 H

NMe2

H Me

Li

N+Me3I–

H Me

OH

F3C H

NMe2

H Me

CF3

O

NMe2

H Me

OH

F3C H

NMe2

H Me

OH

H CF3

[α]D –69.8° (no solvent)1

1a

BuLiether,

hexane

CF3COOEt

ether,–78°ë

3

5 4

CH3I

acetone

2a

+

2b

S

S S S SSRRR

F7C3

The reaction was carried out by a reported proce-dure [4] in an ether–hexane mixture under argon at

−

78

°

C. According to

1

ç

NMR data, the reaction mix-

ture formed after condensation of

1‡

with ethyl trifluo-roacetate contained the starting amine

1

(about 50%), amixture of diastereomeric secondary alcohols

2‡

and

2

b

in a 2 : 1 ratio (yield 50%), and traces of ketone

3

.After workup and evaporation of unreacted amine

1

, themixture was chromatographed on silica gel (elutionwith a 6 : 1 benzene–ethanol mixture) to isolate both

Stereoselective Synthesis and Configuration of (

R

)-[2-(

S

)-(1-

N

,

N

-Dimethylaminoethyl)phenyl]perfluoroalkylmethanols

I. N. Shishkina

a

, V. M. Dem’yanovich

a

, A. A. Kuznetsova

a

, K. A. Potekhin

b

, and

Academician

N. S. Zefirov

a

Received May 13, 2008

DOI:

10.1134/S0012500808110049

a

Moscow State University, Moscow, 119899 Russia

b

Vladimir State Pedagogical University, Vladimir, Russia

CHEMISTRY

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Vol. 423

Part 1

2008

SHISHKINA et al.

diastereomers and a minor amount of ketone

3

, IR(film),

ν

, cm

–1

: 1670

(C=O).

1

H NMR (400 MHz,CDCl

3

, TMS,

δ

, ppm): 1.39 (d, 3H,

ëç

3

CH); 2.14 (s,6H, (CH

3

)

2

N); 4.06 (q, 1H, CH

3

ëç

); 7.21–7.45 (m,5H, C

6

H

5

).

Diastereomeric alcohols

2a

and

2b

are light yellowoily compounds. Their structures and individual statewere confirmed by IR and

1

H NMR spectroscopy.Amino alcohol

2a

,

R

f

0.55 (Silufol, benzene–acetone,6 : 1). IR (film),

ν

, cm

–1

: 3500–3200

(OH).

1

H NMR

(400 MHz,

CDCl

3

, TMS,

δ

, ppm,

J

, Hz): 1.45 (d, 3H,

CH

3

CH,

J

= 6.8); 2.20 (s, 6H, (CH

3

)

2

N); 4.49 (q, 1H,

ëç

3

ëç,

J

= 6.8); 5.06 (q, 1H,

ëF

3

CHOH,

J

= 8.5);7.39–8.30 (m, 5H, C

6

H

5

); 9.50 (br. s, 1H, OH). [

α

]

D

–38.5°

(

c

1

, ethanol); iodomethylate of

2‡

(

4

)

, mp

260°ë

(decomp.),

[

α

]

D

–37.3° (

c

1

, ethanol). Amino alcohol

2b

,

R

f

0.40 (Silufol, benzene–acetone, 6 : 1). IR (film),

ν

, cm

–1

: 3500–3200 (OH). 1H NMR (400 MHz, CDCl3,TMS, δ, ppm, J, Hz): 1.45 (d, 3H, CH3CH, J = 6.8);2.23 (s, 6ç, N(CH3)2); 4.09 (q, 1H, ëç3ëç, J = 6.8);

F(3)

F(1)C(7)

C(6) C(5)

C(4)C(9)

C(11A)

C(12A)C(10A)

N(1)

C(8)C(3)C(2)

C(1)

O(1)

C(13)

F(2) F(7)F(6)

C(14)

F(5)

C(13)

F(3)

F(1)C(12)

F(2)

F(4)C(10)

C(11)

N(1)

C(8)

C(9)C(4)

C(5)C(6)

C(7)O(1)

C(1)C(2) C(3)

(a)

(b)

OLi

NMe2

H Me

C3F7 H

OCH3C

H

6

+(R)(S)

O–

Li F

FO

MeHH

CF3F

F+N

Me

MeMe

H

SN2

Fig. 1. Reduction route of ketone.

Fig. 2. Reduction route of hemiaminal 6.

Fig. 3. Perspective views of (a) iodomethylate 4 molecule and (b) amino alcohol 5 molecule.

OCH3C

H+

(R)

NMe2

MeH

O

Li FF

CF3

F F

O

MeHH NMe2

MeH

C3F7LiO

H

DOKLADY CHEMISTRY Vol. 423 Part 1 2008

STEREOSELECTIVE SYNTHESIS AND CONFIGURATION 281

5.35 (q, 1H, ëF3CHOH, J = 8.5); 7.33–7.57 (m, 6H,ë6ç5 and OH). [α]D –9.9° (c 1, ethanol).

The reaction of 1‡ with ethyl heptafluorobutyrateafforded only one diastereomeric alcohol 5 (yield50%), which crystallized from the reaction mixture asdark crystals, mp 76°ë (from ethanol). IR (film), ν, cm−1:3000–2300 (broad band), 3070. 1H NMR (400 MHz,CDCl3, TMS, δ, ppm, J, Hz): 1.41 (d, 3H, CH3CH,J = 6.8); 2.21 (s, 6H, (CH3)2N); 4.53 (q, 1H, ëç3ëç,J = 6.8); 5.20 and 5.26 (dd, 1H, ëF2CHOH, J = 8.5);7.31–7.40 (m, 5H, C6H5); 11.25 (br. s, 1H, OH). [α]D−40.3° (c 1, ethanol); iodomethylate of 2b, mp 150°ë(decomp.), [α]D –42.4° (c 1, ethanol).

This reaction can be considered as an example of a“domino reaction” in which the ketone formed in thefirst condensation stage is then reduced with participa-tion of the ethoxide anion, which gives off a hydride ion[6]. In the ketones formed, the carbonyl carbon atommay undergo donor–acceptor interaction with the nitro-gen lone pair, similarly to the transannular interactionin some cyclic amino ketones [7]. This is indicated bythe pronounced shift of the carbonyl band in the IRspectrum of ketone 3 (νë=é 1670 cm–1) with respect tothat for phenyl trifluoromethyl ketone (νë=é 1720 cm–1).In addition, it follows from earlier X-ray diffractiondata for 2-[1-(S)-N,N-dimethylaminoethyl]benzophe-none [4] that the carbonyl carbon atom and the dimeth-ylamino-group nitrogen atom are proximate in space.This results in a relatively rigid five-membered ringstructure, which is expected to be attacked from the lesshindered side, i.e., from the hydrogen (rather thanmethyl group) side at the chiral amine center, givingrise to an (R) carbinol center (Fig. 1).

An alternative explanation is also possible: first ahemiaminal is formed and then it is attacked stereospe-cifically by a hydride ion, which leads to nucleophilicSN2 substitution. Figure 2 shows the route of reductionof hemiaminal 6 derived from the ketone formed in thecondensation of 1a with C3F7COOEt. It can be takenthat, in both cases, hydride ion transfer involves a six-membered transition state to give an (R)-configuredcarbinol center. The process stereoselectivity dependson the bulk of the fluoroalkyl group, as can be easilyseen in Fig. 2. Apparently, the hemiaminal is formedstereoselectively, which determines the outcome of thereaction: in the case of trifluoroacetate, the amino alco-hol diastereomers 2a and 2b are formed in a 2 : 1 ratio,while the reaction with heptafluorobutyrate gives onlyone diastereomer 5.

To determine the configuration of the newly formedchiral carbinol center, the iodomethylate of the majordiastereomer of the trifluoromethyl amino alcohol 2‡(4) and the single crystal of 5 were studied by X-ray dif-fraction. The X-ray diffraction data attest unambigu-ously to the (R) configuration of the carbinol centersin 4 (and, hence, in 2a) and 5 on the basis of the known(S) configuration of the chiral center of the starting

amine 1 (Figs. 3a, 3b). This confirms our assumptionconcerning the reaction stereochemistry. The absoluteconfiguration of compound 4 was also determinedobjectively based on the Flack parameter [8].

The single-crystal X-ray diffraction study of 4 and 5was carried out at 100 K on a Bruker SMART APEX IICCD automated three-circle diffractometer with a two-dimensional detector (MoKα radiation, graphite mono-chromator, ϕ and ω scan modes). The crystallographicdata and some X-ray experiment details for 4 and 5 aresummarized in the table. Both structures were solvedby direct methods using theSHELXTL Plus software.The OH hydrogen atoms were revealed objectivelyfrom the difference electron density synthesis. Thepositions of other hydrogen atoms were calculated andrefined in the riding model. The structures were refinedby the least-squares method in the full-matrix anisotro-pic (for OH hydrogen atoms, isotropic) approximation.

Crystallographic data and X-ray experiment details for 4and 5

ParameterCompound

4 5

Molecular formula C13H19F3NO+I– C14H16F7NO

Molecular weight 389.19 347.28

System Orthorhombic

Space group P212121

a, Å 10.3367(3) 10.2998(6)

b, Å 10.7516(3) 11.1931(8)

c, Å 13.8522(4) 13.5220(9)

V, Å3 1539.48(8) 1558.9(2)

Z 4

Data collection rangeover θ, deg

2.40–29.00 2.36–29.00

Number of measured re-flections

7671 10732

Number of independent reflections

3952 4140

Degree of data collec-tion, %

99.6 100.0

Refinement method Full-matrix least-squares on F2

Number of reflec-tions/constraints/param-eters

3952/0/211 4140/10/243

S on F2 1.054 1.032

R [I > 2σ(I)] R1 0.0181 R1 0.0504

wR2 0.0397 wR2 0.1136

R (all data) R1 0.0195 R1 0.0707

wR2 0.0402 wR2 0.1248

Absolute structure pa-rameter

0.00 (0.02) –

282

DOKLADY CHEMISTRY Vol. 423 Part 1 2008

SHISHKINA et al.

The full set of X-ray diffraction data is depositedwith the Cambridge Crystallographic Data Centre(CCDC 692977 for 4 and CCDC 692976 for 5), 12Union Road, Cambridge CB2 1EZ, UK; fax: + 44-1223/336-033; e-mail: deposit@ccdc.cam.ac.uk;http://www. ccdc.cam.ac.uk.

ACKNOWLEDGMENTSThis work was supported by the Council for Grants

of the President of the Russian Federation for Supportof Leading Scientific Schools (grant no. NSh–5538.2008.3).

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